Mechanisms of cardiovascular disorders in patients with chronic kidney disease: a process related to accelerated senescence

Cardiovascular diseases (CVDs), especially those involving a systemic inflammatory process such as atherosclerosis, remain the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). CKD is a systemic condition affecting approximately 10% of the general population. The prevalence of CKD has increased over the past decades because of the aging of the population worldwide. Indeed, CVDs in patients with CKD constitute a premature form of CVD observed in the general population. Multiple studies indicate that patients with renal disease undergo accelerated aging, which precipitates the appearance of pathologies, including CVDs, usually associated with advanced age. In this review, we discuss several aspects that characterize CKD-associated CVDs, such as etiopathogenic elements that CKD patients share with the general population, changes in the cellular balance of reactive oxygen species (ROS), and the associated process of cellular senescence. Uremiaassociated aging is linked with numerous changes at the cellular and molecular level. These changes are similar to those observed in the normal process of physiologic aging. We also discuss new perspectives in the study of CKD-associated CVDs and epigenetic alterations in intercellular signaling, mediated by microRNAs and/or extracellular vesicles (EVs), which promote vascular damage and subsequent development of CVD. Understanding the processes and factors involved in accelerated senescence and other abnormal intercellular signaling will identify new therapeutic targets and lead to improved methods of diagnosis and monitoring for patients with CKD-associated CVDs

Innovación metodológica en la impartición de seminarios de refuerzo sobre el aprendizaje teórico

El presente proyecto tiene como objetivo principal la innovación en la metodología con la que se imparten los seminarios para mejorar la adquisición de competencias y facilitar la evaluación formativa en la asignatura de Fisiología animal.Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasFALSEsubmitte

The Role of Immune Cells in Oxi-Inflamm-Aging

Aging is the result of the deterioration of the homeostatic systems (nervous, endocrine, and immune systems), which preserve the organism’s health. We propose that the age-related impairment of these systems is due to the establishment of a chronic oxidative stress situation that leads to low-grade chronic inflammation throughout the immune system’s activity. It is known that the immune system weakens with age, which increases morbidity and mortality. In this context, we describe how the function of immune cells can be used as an indicator of the rate of aging of an individual. In addition to this passive role as a marker, we describe how the immune system can work as a driver of aging by amplifying the oxidative-inflammatory stress associated with aging (oxi-inflamm-aging) and inducing senescence in far tissue cells. Further supporting our theory, we discuss how certain lifestyle conditions (such as social environment, nutrition, or exercise) can have an impact on longevity by affecting the oxidative and inflammatory state of immune cells, regulating immunosenescence and its contribution to oxi-inflamm-aging

Oxidative-Inflammatory Stress in Immune Cells from Adult Mice with Premature Aging

Oxidative and inflammatory stresses are closely related processes, which contribute to age-associated impairments that affect the regulatory systems such as the immune system and its immunosenescence. Therefore, the aim of this work was to confirm whether an oxidative/inflammatory stress occurs in immune cells from adult mice with premature aging, similar to that shown in leukocytes from chronologically old animals, and if this results in immunosenescence. Several oxidants/antioxidants and inflammatory/anti-inflammatory cytokines were analyzed in peritoneal leukocytes from adult female CD1 mice in two models of premature aging—(a) prematurely aging mice (PAM) and (b) mice with the deletion of a single allele (hemi-zygotic: HZ) of the tyrosine hydroxylase (th) gene (TH-HZ), together with cells from chronologically old animals. Several immune function parameters were also studied in peritoneal phagocytes and lymphocytes. The same oxidants and antioxidants were also analyzed in spleen and thymus leukocytes. The results showed that the immune cells of PAM and TH-HZ mice presented lower values of antioxidant defenses and higher values of oxidants/pro-inflammatory cytokines than cells from corresponding controls, and similar to those in cells from old animals. Moreover, premature immunosenescence in peritoneal leukocytes from both PAM and TH-HZ mice was also observed. In conclusion, adult PAM and TH-HZ mice showed oxidative stress in their immune cells, which would explain their immunosenescence

Premature aging in behavior and immune functions in tyrosine hydroxylase haploinsufficient female mice. A longitudinal study

Aging is accompanied by impairment in the nervous, immune, and endocrine systems as well as in neuroimmunoendocrine communication. In this context, there is an age-related alteration of the physiological response to acute stress, which is modulated by catecholamine (CA), final products of the sympathetic-adreno-medullary axis. The involvement of CA in essential functions of the nervous system is consistent with the neuropsychological deficits found in mice with haploinsufficiency (hemizygous; HZ) of tyrosine hydroxylase (TH) enzyme (TH-HZ). However, other possible alterations in regulatory systems have not been studied in these animals. The aim of the present work was to analyze whether adult TH-HZ female mice presented the impairment of behavioral traits and immunological responses that occurs with aging and whether they had affected their mean lifespan. ICR-CD1 female TH-HZ and wild type (WT) mice were used in a longitudinal study. Behavioral tests were performed on adult and old mice in order to evaluate their sensorimotor abilities and exploratory capacity, as well as anxiety-like behaviors. At the ages of 2 ± 1, 4 ± 1, 9 ± 1, 13 ± 1 and 20 ± 1 months, peritoneal leukocytes were extracted and several immune functions were assessed (phagocytic capacity, Natural Killer (NK) cytotoxicity, and lymphoproliferative response to lipopolysaccharide (LPS) and concanavalin A (ConA)). In addition, several oxidative stress parameters (catalase, glutathione reductase and glutathione peroxidase activities, and reduced glutathione (GSH) concentrations as antioxidant compounds as well as xanthine oxidase activity, oxidized glutathione (GSSG) concentrations, and GSSG/GSH ratio as oxidants) were analyzed. As inflammatory stress parameters TNF-alpha and IL-10 concentrations, and TNF-alpha/IL-10 ratios as inflammatory/anti-inflammatory markers, were measured. Animals were maintained in standard conditions until their natural death. The results indicate that adult TH-HZ mice presented worse sensorimotor abilities and exploratory capacity than their WT littermates as well as greater anxiety-like behaviors. With regards to the immune system, adult TH-HZ animals exhibited lower values of phagocytic capacity, NK cytotoxicity, and lymphoproliferative response to LPS and ConA than WT mice. Moreover, immune cells of TH-HZ mice showed higher oxidative and inflammatory stress than those of WT animals. Although these differences between TH-HZ and WT, in general, decreased with aging, this premature immunosenescence and impairment of behavior of TH-HZ mice was accompanied by a shorter mean lifespan in comparison to WT counterparts. In conclusion, haploinsufficiency of th gene in female mice appears to provoke premature aging of the regulatory systems affecting mean lifespan

A short social interaction between adult and old mice improves the homeostatic systems and increases healthy longevity

The aging process can be influenced by environmental factors, such as the social environment. The continuous cohabitation of the chronologically old mice with adult animals improves them at the behavioral level, immune function, oxidative stress and longevity, but causes a deterioration of these parameters in adults. Therefore, the objective of the study was to study whether the coexistence for only 15 min a day of old mice with adult mice, can produce that improvement and greater longevity in old animals without causing deterioration in adults. For that, old and adult CD1 female mice, after two months of that social interaction, were submitted to a behavioral battery and then peritoneal leukocytes were collected to assess several immune functions, oxidative and inflammatory stress parameters as well as catecholamine concentrations. When the adult mice reached old age, the same parameters were again analyzed. The life span of each animal was also recorded. Plasmatic concentration of oxytocin was also studied. The results showed that old mice presented better behavioral capacity, immunity and oxi-inflammatory state after this social interaction with adult animals, and consequently an extended life span. Adult mice, in general, did not show any changes after social interaction with old animals, but when they achieved old age, improvements of some parameters and of longevity were observed in comparison with animals that never had a that social interaction. In conclusion, a short social interaction between old and adult individuals can be an excellent strategy for improving in both the health state and longevity

Social environment ameliorates behavioral and immune impairments in tyrosine hydroxylase haploinsufficient female mice

The social environment can influence the functional capacity of nervous and immune systems, and consequently the state of health, especially in aged individuals. Adult female tyrosine hydroxylase haploinsufficient (TH-HZ) mice exhibit behavioral impairments, premature immunosenescence and oxidative- inflammatory stress. All these deteriorations are associated with a lower lifespan than wild type (WT) counterparts. The aim was to analyze whether the cohabitation with WT animals could revert or at least ameliorate the deterioration in the nervous and immune systems that female TH-HZ mice show at adult age. Female TH-HZ and WT mice at age of 3–4 weeks were divided into following groups: control TH-HZ (5 TH-HZ mice in the cage; THHZ100%), control WT (5 WT mice in the cage; WT100%), TH-HZ > 50% and WT 50% (2 TH-HZ and 5 WT mice in each cage). At the age of 37–38 weeks, all mice were submitted to a battery of behavioral tests, evaluating sensorimotor abilities, exploratory capacities and anxiety-like behaviors. Subsequently, peritoneal leukocytes were extracted and several immune functions as well as oxidative and inflammatory stress parameters were analyzed. The results showed that the TH-HZ < 50% group had improved behavioral responses, especially anxiety-like behaviors, and the immunosenescence and oxidative stress of their peritoneal leukocytes were ameliorated. However, WT mice that cohabited with TH-HZ mice presented higher anxiety-like behaviors and deterioration in immune functions and in their inflammatory stress parameters. Thus, this social environment is capable of ameliorating the impairments associated with a haploinsufficiency of the th gene

Social environment improves immune function and redox state in several organs from prematurely aging female mice and increases their lifespan

Aging is associated with a chronic oxidative stress (increase of oxidants and decrease of antioxidants), which contributes to immunosenescence and therefore shorter longevity. Nevertheless, a positive social network has been related to the adequate maintenance of health and deceleration of aging. Adult prematurely aging mice (PAM) are characterized by their inadequate stress response to a T-maze, showing premature immunosenescence and oxidative stress establishment. These impairments contribute to shorter life spans in comparison to exceptional non-PAM (ENPAM). However, it is not known whether these characteristics of PAM could be prevented by a positive cohabitation. Therefore, the aim of the present work was to determine if the premature immunosenescence and oxidative stress shown by PAM could be avoided by the cohabitation with ENPAM, increasing their life span. Female CD1 PAM and ENPAM were divided into three experimental groups: PAM controls, ENPAM controls and a social environment experimental group, containing in the same cage ENPAM and PAM (proportion 5/2, respectively). After 2 months, mice were sacrificed and spleen, thymus, liver and heart removed. Later, several immune functions as well as oxidative stress parameters were assessed in spleen and thymus leukocytes. Also, several oxidative stress parameters were analyzed in liver and heart. The results showed that PAM, after co-housing with ENPAM, had improved immune functions and redox balance in spleen and thymus leukocytes. This improvement of redox state was also observed in liver and heart. Furthermore, all these positive effects seem to be related to the increased life span of PAM

Endothelial senescence and the chronic vascular diseases: challenges and therapeutic opportunities in atherosclerosis

Atherosclerosis is probably one of the paradigms of disease linked to aging. Underlying the physiopathology of atherosclerosis are cellular senescence, oxidative stress, and inflammation. These factors are increased in the elderly and from chronic disease patients. Elevated levels of oxidative stress affect cellular function and metabolism, inducing senescence. This senescence modifies the cell phenotype into a senescent secretory phenotype. This phenotype activates immune cells, leading to chronic systemic inflammation. Moreover, due to their secretory phenotype, senescence cells present an increased release of highlighted extracellular vesicles that will change nearby/neighborhood cells and paracrine signaling. For this reason, searching for specific senescent cell biomarkers and therapies against the development/killing of senescent cells has become relevant. Recently, senomorphic and senolityc drugs have become relevant in slowing down or eliminating senescence cells. However, even though they have shown promising results in experimental studies, their clinical use is still yet to be determined

The ratio of prematurely aging to non-prematurely aging mice cohabiting, conditions their behavior, immunity and lifespan

Adult prematurely aging mice (PAM) show behavioral deterioration, premature immunosenescence and increased oxidative stress, impairments that are associated with their shorter lifespan, compared to the corresponding exceptional non-prematurely aging mice (ENPAM). When PAM live in a predominantly ENPAM environment (2/5, respectively) they exhibit an improvement of immunity and redox state in their spleen and thymus leukocytes, and an increased lifespan. Nevertheless, it is unknown if other PAM/ENPAM ratios could affect behavioral and peritoneal leukocyte functions of PAM and change their lifespan. ENPAM and PAM were divided into the following groups: C-ENPAM (8 ENPAM in the cage); C-PAM (8 PAM in the cage); ENPAM > 50% and PAM 50% and ENPAM 50%, PAM = 50% and PAM < 50% exhibited better behavioral responses, immunity and redox states in their peritoneal leukocytes than C-PAM. This improvement was higher when the number of ENPAM in the cage was increased, with most of the parameters in PAM < 50% reaching similar values to those in C-ENPAM, and an increased lifespan. However, ENPAM that cohabited with PAM showed, in general, an impairment of parameters studied. In conclusion, the PAM/ENPAM cohabitation ratio is relevant to behavior and immunit